Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurotensin (NT) receptor-3/sortilin (NTR3) belongs to the new receptor family of VPS10P domain containing receptors. The NTR3 is expressed in all cancer cells on which NT activates cell growth and its cellular location is mainly intracellular within the endoplasmic reticulum and the trans-Golgi network. However, the NTR3 is also present at the cell surface of the HT29 cell line from which it is released by a mechanism activated by phorbol 12-myristate 13-acetate (PMA). The shedding of the NTR3 is sensitive to protein kinase C (PKC) and mitogen-activated protein (MAP) kinase inhibitors and to 1,10-phenanthroline and BB3103, suggesting the activation of zinc-metalloproteases and the ADAM10 (a desintegrin and metalloprotease). The shedding of the membrane NTR3 leads to a soluble protein able to bind exogenous NT, suggesting a role of this process in the biological activity of the peptide.
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PMID:Shedding of the luminal domain of the neurotensin receptor-3/sortilin in the HT29 cell line. 1241 19

Many excitatory neurotransmitters and neuropeptides regulate the activity of neuronal and endocrine cells by modulating voltage-operated Ca2+ channels. Paradoxically, however, excitatory neuromediators that provoke mobilization of intracellular calcium from inositol trisphosphate (IP3)-sensitive stores usually inhibit voltage-gated Ca2+ currents. We have recently demonstrated that neurotensin (NT) stimulates the electrical and secretory activities of frog pituitary melanotrophs, and increases intracellular calcium concentration in these cells. In the present study, we have investigated the effects of NT on Ca2+ currents in cultured frog melanotrophs by using the perforated patch-clamp technique. Frog neurotensin (f NT) reduced the amplitude and facilitated the inactivation of both L- and N-type Ca2+ currents. Application of the membrane-permeant Ca2+ chelator BAPTA-AM, the sarcoendoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin, or the IP3 receptor antagonist 2-APB suppressed the reduction of Ca2+ currents induced by f NT. Incubation of melanotrophs with the diacylglycerol analogue PMA, which causes desensitization of protein kinase C (PKC), or with the PKC inhibitors chelerythrine and calphostin C, reduced the inhibitory effect of f NT. The NT-induced action potential waveforms, applied as voltage-clamp commands, decreased the amplitude of Ca2+ currents, and enhanced Ca2+ influx by increasing the Ca2+ spike frequency. Altogether, these data indicate that the inhibitory effect of f NT on Ca2+ currents results from activation of the IP3/PKC pathway. The observation that NT controls Ca2+ signalling through both amplitude and frequency modulations of Ca2+ currents suggests that NT might induce spacial and temporal changes of intracellular Ca2+ concentration leading to stimulation of exocytosis.
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PMID:Neurotensin modulates the amplitude and frequency of voltage-activated Ca2+ currents in frog pituitary melanotrophs: implication of the inositol triphosphate/protein kinase C pathway. 1245 54

The protein kinase D (PKD) family consists of three serine/threonine protein kinases: PKC mu/PKD, PKD2, and PKC nu/PKD3. While PKD has been the focus of most studies to date, no information is available on the intracellular distribution of PKD2. Consequently, we examined the mechanism that regulates its intracellular distribution in human pancreatic carcinoma Panc-1 cells. Analysis of the intracellular steady-state distribution of fluorescent-tagged PKD2 in unstimulated cells indicated that this kinase is predominantly cytoplasmic. Cell stimulation with the G protein-coupled receptor agonist neurotensin induced a rapid and reversible plasma membrane translocation of PKD2 by a mechanism that requires PKC activity. In contrast to the other PKD isoenzymes, PKD2 activation did not induce its redistribution from the cytoplasm to the nucleus. Thus, this study demonstrates that the regulation of the distribution of PKD2 is distinct from other PKD isoenzymes, and suggests that the differential spatio-temporal localization of these signaling molecules regulates their specific signaling properties.
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PMID:Intracellular redistribution of protein kinase D2 in response to G-protein-coupled receptor agonists. 1264 43

The protein kinase D (PKD) family consists of three serine/threonine kinases: PKC micro/PKD, PKD2, and PKCnu/PKD3. Whereas PKD has been the focus of most studies, virtually nothing is known about the effect of G protein-coupled receptor agonists (GPCR) on the regulatory properties and intracellular distribution of PKD3. Consequently, we examined the mechanism that mediates its activation and intracellular distribution. GPCR agonists induced a rapid activation of PKD3 by a protein kinase C (PKC)-dependent pathway that leads to the phosphorylation of the activation loop of PKD3. Comparison of the steady-state distribution of endogenous or tagged PKD3 versus PKD and PKD2 in unstimulated cells indicated that whereas PKD and PKD2 are predominantly cytoplasmic, PKD3 is present both in the nucleus and cytoplasm. This distribution of PKD3 results from its continuous shuttling between both compartments by a mechanism that requires a nuclear import receptor and a competent CRM1-nuclear export pathway. Cell stimulation with the GPCR agonist neurotensin induced a rapid and reversible plasma membrane translocation of PKD3 that is PKC-dependent. Interestingly, the nuclear accumulation of PKD3 can be dramatically enhanced in response to its activation. Thus, this study demonstrates that the intracellular distribution of PKD isoenzymes are distinct, and suggests that their signaling properties are regulated by differential localization.
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PMID:Protein kinase C nu/protein kinase D3 nuclear localization, catalytic activation, and intracellular redistribution in response to G protein-coupled receptor agonists. 1267 44

Neuropeptides and their corresponding G protein-coupled receptors are increasingly implicated in the autocrine/paracrine stimulation of growth of human cancers. Using K-Ras mutated human pancreatic ductal adenocarcinoma cell line PANC-1 as a model system, we demonstrate that neurotensin (NT) induced translocation of phosphorylated extracellular signal-regulated kinases (ERK-1 and ERK-2) to the nucleus, rapid dose-dependent activation of dual-specificity mitogen and ERK-1 and ERK-2 kinase-1/2 (MEK-1/2), and striking stimulation of c-Raf-1 but not pan-Ras. Furthermore, treatment of PANC-1 cells with protein kinase C (PKC) inhibitors, GF-1 and Ro 31-8220, completely abrogated NT-induced ERK-1 and ERK-2 activation, and significantly attenuated NT-induced c-Raf-1 stimulation. Interestingly, NT did not stimulate epidermal growth factor receptor transactivation, and epidermal growth factor receptor tyrosine kinase or Src inhibitors did not affect NT-induced ERK activation in PANC-1 cells. Our results indicate that NT potently stimulates c-Raf-1-MEK-ERK in PANC-1 cells through a PKC-dependent signaling pathway. Furthermore, we show that NT-induced DNA synthesis in PANC-1 cells is ERK-dependent. Finally, we demonstrate that NT stimulated clonal growth of PANC-1 cells in semisolid medium, which is abrogated by both GF-1 and the MEK-1/2 inhibitor, U0126. Collectively our results suggest that PKC-mediated stimulation of ERK-1 and ERK-2 play a pivotal role in NT-induced growth of PANC-1 cells harboring activating K-Ras mutation.
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PMID:Neurotensin stimulates protein kinase C-dependent mitogenic signaling in human pancreatic carcinoma cell line PANC-1. 1275 Feb 55

Neurotensin (NT) is a potent stimulator of electrical and secretory activities in frog pituitary melanotrophs. The aim of the present study was to characterize the transduction pathways associated with activation of NT receptors in frog melanotrophs. Application of synthetic frog NT (fNT) increased the cytosolic calcium concentration ([Ca2+]c) and stimulated the formation of inositol trisphosphate (IP3). The phospholipase C inhibitor U-73122 blocked the electrophysiological and secretory effects of fNT. Intracellular application of the IP3 receptor antagonist heparin abolished fNT-induced electrical activity. Suppression of Ca2+ in the incubation medium markedly reduced the effect of NT on [Ca2+]c, firing rate, and alpha-melanocyte-stimulating hormone (alphaMSH) secretion. Similarly, the inhibitor of IP3-induced Ca2+ release and store-operated Ca2+ channels, 2-Aminoethoxydiphenylborane, and the nonselective Ca2+ channel blockers GdCl3 and NiCl2, attenuated the [Ca2+]c increase and the electrical and secretory responses evoked by fNT. Coapplication of the L- and N-type Ca2+ channel blockers nifedipine and omega-CgTx GVIA reduced the effects of fNT on action potential discharge, [Ca2+]c increase, and alphaMSH release. The protein kinase C (PKC) inhibitors, PKC-(19-31) and chelerythrine, reduced the electrophysiological and secretory responses induced by iterative applications of fNT. Collectively, these results demonstrate that, in frog melanotrophs, NT stimulates the phospholipase C/PKC pathway and increases [Ca2+]c. Both Ca2+ release from intracellular stores and Ca2+ influx through L- and N-type Ca2+ channels are involved in fNT-induced alphaMSH secretion. In addition, the present data indicate that PKC plays a crucial role in maintenance of the responsiveness of melanotrophs to NT.
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PMID:Neurotensin stimulates both calcium mobilization from inositol trisphosphate-sensitive intracellular stores and calcium influx through membrane channels in frog pituitary melanotrophs. 1450 May 81

Primary cultures of cortical neurons were employed to investigate the modulatory effects of neurotensin on glutamate excitotoxicity and the possible neuroprotective actions of the neurotensin receptor antagonist SR48692. NT(1-13) and its biologically active fragment NT(8-13) at 10 nM (30 min) increased endogenous glutamate levels. The inactive fragment NT(1-7) (10-100 nM; 30 min) was ineffective. SR48692, applied 20 min before NT and maintained in contact with cells during NT exposure as well as a low calcium medium (from the onset of the experiment) prevented the NT(1-13)-induced increase in extracellular glutamate levels. The addition of NMDA (0.01-10 micro M; 10 min) to the medium concentration-dependently increased extracellular glutamate levels. When 0.1 nM NT(1-13) was added in combination with 0.01 micro M NMDA, in concentrations by themselves ineffective, a significant increase in glutamate levels was observed. SR48692 at 100 nM counteracted the increase in glutamate levels induced by 0.1 nM NT(1-13) plus 0.01 micro M NMDA. The inhibitor of the protein kinase C (PKC) calphostin C (0.1 micro M; 10 min before NT) prevented the increase in glutamate levels induced by the combined treatments. The morphological analysis indicated that 10 nM NT(1-13) enhanced the glutamate (10 min)-induced apoptosis. The peptide was added 30 min prior to glutamate and maintained in contact with cells during the glutamate exposure. The presence of 100 nM SR48692 (20 min before NT) antagonized this effect of NT(1-13). These findings support the view of a pathophysiological role for NT in the cerebral cortex. Thus, under pathological conditions NT by enhancing glutamate outflow and by amplifying the NMDA-mediated glutamate signaling may be involved in increasing the degeneration of cortical neurons.
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PMID:Neurotensin enhances endogenous extracellular glutamate levels in primary cultures of rat cortical neurons: involvement of neurotensin receptor in NMDA induced excitotoxicity. 1502 50

Neurotensin (NT) is a gut peptide that plays an important role in gastrointestinal (GI) secretion, motility, and growth as well as the proliferation of NT receptor positive cancers. Secretion of NT is regulated by phorbol ester-sensitive protein kinase C (PKC) isoforms-alpha and -delta and may involve protein kinase D (PKD). The purpose of our present study was: (i) to define the role of PKD in NT release from BON endocrine cells and (ii) to delineate the upstream signaling mechanisms mediating this effect. Here, we demonstrate that small interfering RNA (siRNA) targeted against PKD dramatically inhibited both basal and PMA-stimulated NT secretion; NT release is significantly increased by overexpression of PKD. PKC-alpha and -delta siRNA attenuated PKD activity, whereas overexpression of PKC-alpha and -delta enhanced PKD activity. Rho kinase (ROK) siRNA significantly inhibited NT secretion, whereas overexpression of ROKalpha effectively increased NT release. Rho protein inhibitor C3 dramatically inhibited both NT secretion and PKD activity. In conclusion, our results demonstrate that PKD activation plays a central role in NT peptide secretion; upstream regulators of PKD include PKC-alpha and -delta and Rho/ROK. Importantly, our results identify novel signaling pathways, which culminate in gut peptide release.
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PMID:The role of protein kinase D in neurotensin secretion mediated by protein kinase C-alpha/-delta and Rho/Rho kinase. 1512 66

The mechanism by which neurotensin (NT) promotes the growth of prostate cancer epithelial cells is not yet defined. Here, androgen-independent PC3 cells, which express high levels of the type 1 NT-receptor (NTR1), are used to examine the involvement of epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (ERK, SAPK/JNK and p38), PI3 kinase and PKC in the mitogenic effect of NT. NT dose dependently (0.1-30 nM) enhanced phosphorylation of EGFR, ERK and Akt, reaching maximal levels within 3 min as measured by Western blotting. These effects were associated with an accumulation of EGF-like substance(s) in the medium (assayed by EGFR binding) and a 2-fold increase in DNA synthesis (assayed by [3H]thymidine incorporation). The DNA synthesis enhancement by NT was non-additive with that of EGF. The NT-induced stimulation of EGFR/ERK/Akt phosphorylation and DNA synthesis was inhibited by EGFR-tyrosine kinase inhibitors (AG1478, PD153035), metallo-endopeptidase inhibitor phosphoramidon and by heparin, but not by neutralizing anti-EGF antibody. Thus, transactivation of EGFR by NT involved heparin-binding EGF (HB-EGF or amphiregulin) rather than EGF. The effects of NT on EGFR/ERK/Akt activation and DNA synthesis were attenuated by PLC-inhibitor (U73122), PKC-inhibitors (bisindolylmaleimide, staurosporine, rottlerin), MEK inhibitor (U0126) and PI3 kinase inhibitors (wortmannin, LY 294002). We conclude that NT stimulated mitogenesis in PC3 cells by a PKC-dependent ligand-mediated transactivation of EGFR, which led to stimulation of the Raf-MEK-ERK pathway in a PI3 kinase-dependent manner.
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PMID:Involvement of MAP-kinase, PI3-kinase and EGF-receptor in the stimulatory effect of Neurotensin on DNA synthesis in PC3 cells. 1517 34

Neurotensin has been shown to influence growth in a number of cancerous and non-cancerous cells and to enhance the proliferative effects of growth factors without itself inducing proliferation. Here we show that neurotensin potentiates the proliferative effects of insulin on IMR90 human fibroblasts in a concentration and neurotensin receptor type 1-dependent manner. This potentiating effect of neurotensin was blocked by inhibitors of phospholipase C and protein kinase C, was accompanied by an increase in the level of soluble inositol phosphates and did not involve an autocrine factor. These results show that neurotensin can enhance insulin-dependent proliferation of human fibroblasts and suggest a possible role for neurotensin in tissue growth and repair.
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PMID:The effect of neurotensin on insulin-induced proliferation of human fibroblasts. 1524 76


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